Non-mutagenic Ru(ii) complexes: cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding

Autor(es):Mostrar menos -

da Silva, Monize M. ^[1] ; de Camargo, Mariana S. ^[2] ; Correa, Rodrigo S. ^[3] ; Castelli, Silvia ^[1] ; De Grandis, Rone A. ^[4] ; Takarada, Jessica E. ^[1] ; Varanda, Eliana A. ^[4] ; Castellano, Eduardo E. ^[5] ; Deflon, Victor M. ^[6] ; Cominetti, Marcia R. ^[7] ; Desideri, Alessandro ^[1] ; Batista, Alzir A. ^[2]

Afiliação do(s) autor(es)

^[1] Univ TorVergatadi Roma, Dipartimentodi Biol, I-00133 Rome - Italy

^[2] Univ Fed Sao Carlos, Dept Quim, CP 676, BR-13565905 Sao Carlos, SP - Brazil

^[3] Univ Fed Ouro Preto, Dept Quim, BR-35400000 Ouro Preto, MG - Brazil

^[4] UNESP, Fac Ciencias Farmaceut, Dept Ciencias Biol, BR-14801902 Araraquara, SP - Brazil

^[5] Univ Sao Paulo, Inst Fis, CP 369, BR-13560970 Sao Carlos, SP - Brazil

^[6] Univ Sao Paulo, Inst Quim Sao Carlos, CP 780, BR-13560970 Sao Carlos, SP - Brazil

^[7] Univ Fed Sao Carlos, Dept Gerontol, CP 676, BR-13565905 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: DALTON TRANSACTIONS; v. 48, n. 39, p. 14885-14897, OCT 21 2019.
• Citações Web of Science: 0

Resumo

Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells. These complexes are named {[}Ru(tzdt)(bipy)(dppb)]PF6 (1), {[}Ru(mmi)(bipy)(dppb)]PF6 (2), {[}Ru(dmp)(bipy)(dppb)]PF6 (3), {[}Ru(mpca)(bipy)(dppb)]PF6 (4) and {[}Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2 `-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1-5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1-5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs. (AU)

• Processo FAPESP: 16/16312-0 - Citotoxidade e mecanismo de ação de complexos de rutênio contendo produtos naturais ou derivados
• Beneficiário: Alzir Azevedo Batista
• Modalidade de apoio: Auxílio à Pesquisa - Regular